Novel dimeric bis(7)-tacrine proton-dependently inhibits NMDA-activated currents

Journal Article · Fri Sep 21 00:00:00 EDT 2007 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2007.07.043· OSTI ID:20991549

Luo, Jialie ^[1]; Li, Wenming ^[1]; Liu, Yuwei ^[2]; Zhang, Wei ^[3]; Fu, Hongjun ^[1]; Lee, Nelson T.K. ^[1]; Yu, Hua ^[1]; Pang, Yuanping ^[4]; Huang, Pingbo ^[3]; Xia, Jun ^[1]; Li, Zhi-Wang ^[2]; Li, Chaoying ^[2]; Han, Yifan ^[1]

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1. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon (Hong Kong)
2. Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030 (China)
3. Department of Biology, Hong Kong University of Science and Technology, Kowloon (Hong Kong)
4. Mayo Cancer Center, Department of Pharmacology, Mayo Clinic, Rochester, MN 55905 (United States)

Bis(7)-tacrine has been shown to prevent glutamate-induced neuronal apoptosis by blocking NMDA receptors. However, the characteristics of the inhibition have not been fully elucidated. In this study, we further characterize the features of bis(7)-tacrine inhibition of NMDA-activated current in cultured rat hippocampal neurons. The results show that with the increase of extracellular pH, the inhibitory effect decreases dramatically. At pH 8.0, the concentration-response curve of bis(7)-tacrine is shifted rightwards with the IC{sub 50} value increased from 0.19 {+-} 0.03 {mu}M to 0.41 {+-} 0.04 {mu}M. In addition, bis(7)-tacrine shifts the proton inhibition curve rightwards. Furthermore, the inhibitory effect of bis(7)-tacrine is not altered by the presence of the NMDA receptor proton sensor shield spermidine. These results indicate that bis(7)-tacrine inhibits NMDA-activated current in a pH-dependent manner by sensitizing NMDA receptors to proton inhibition, rendering it potentially beneficial therapeutic effects under acidic conditions associated with stroke and ischemia.

• OSTI ID: 20991549
• Journal Information: Biochemical and Biophysical Research Communications, Vol. 361, Issue 2; Other Information: DOI: 10.1016/j.bbrc.2007.07.043; PII: S0006-291X(07)01525-2; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
HIPPOCAMPUS
INHIBITION
ISCHEMIA
NERVE CELLS
PH VALUE
PROTONS
RATS
RECEPTORS
SPERMIDINE